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Repeated Application of 4-Aminopyridine Provoke an Increase in Entorhinal Cortex Excitability and Rearrange AMPA and Kainate Receptors

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Abstract

Entorhinal cortex is a highly epilepsy-prone brain region. Effects of repetitive seizures on ionotropic glutamate receptors (iGluRs) were investigated in rat entorhinal cortex slices. Seizures were induced by daily administration of 4-aminopyridine (4-AP). Electrophysiological, pharmacological and histological investigations were carried out to determine changes in synaptic efficacy and in sensitivity of iGluRs due to recurring seizures. Repeated 4-AP-induced seizures increased the amplitude of evoked synaptic field responses in rat entorhinal cortical slices. While vulnerability to inhibition of AMPA receptors by the specific antagonist GYKI 52466 was slightly reduced, responsiveness to NMDA receptor antagonist APV remained unaffected. Testing of bivalent cation permeability of iGluRs revealed reduced Ca2+-influx through non-NMDA receptors. According to the semi-quantitative histoblot analysis GluA1–4, GluA1, GluA2, GluK5, GluN1 and GluN2A subunit protein expression differently altered. While there was a marked decrease in the level of GluA1–4, GluA2 and GluK5 receptor subunits, GluA1 and GluN2A protein levels moderately increased. The results indicate that brief convulsions, repeated daily for 10 days can increase overall entorhinal cortex excitability despite a reduction in AMPA/kainate receptor activity, probably through the alteration of local network susceptibility.

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Acknowledgments

This research was supported by Grant from the Biotechnology and Biological Sciences Research Council, UK (Grant BB/J015938/1 to E.M.) and from TAMOP (4.2.2/A-11/1/KONV-2012-0052 to A.M.).

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The authors declare that they have no conflict of interests.

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Authors and Affiliations

  1. Department of Physiology and Neurobiology, Institute of Biology, Eötvös Loránd University, Pázmány Péter sétány 1/c, Budapest, 1117, Hungary

    Sándor Borbély, Dávid Czégé & Ildikó Világi

  2. School of Physiology and Pharmacology, University of Bristol, Medical Sciences Building, University Walk, Bristol, BS8 1TD, UK

    Elek Molnár

  3. Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Szeged, Kossuth Lajos sgt. 40, Szeged, 6724, Hungary

    Endre Dobó & András Mihály

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  1. Sándor Borbély
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Correspondence to Sándor Borbély.

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Borbély, S., Czégé, D., Molnár, E. et al. Repeated Application of 4-Aminopyridine Provoke an Increase in Entorhinal Cortex Excitability and Rearrange AMPA and Kainate Receptors. Neurotox Res 27, 441–452 (2015). https://doi.org/10.1007/s12640-014-9515-7

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  • DOI: https://doi.org/10.1007/s12640-014-9515-7

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